1. Field of the Invention
The present invention relates to processes for the synthesis of antiviral N-9 substituted guanine compounds.
2. Background Information and Related Disclosures
Many synthetic N-substituted derivatives of purines and related nucleosides have been shown to exhibit significant antiviral properties. Most notable are the N-9 alkylated products 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (i.e. ganciclovir) and 9-[(2-hydroxyethoxy)methyl]guanine, (i.e. acyclovir). It is clearly desirable to have inexpensive and efficient processes for manufacturing these and similar compounds.
The usefulness of any process for manufacturing chemical compounds is gauged by several factors. For example, starting materials should be as simple structurally as feasible (so as to keep their costs low). The process is more efficient if intermediates do not require isolation and/or purification, since these procedures result in additional steps and lower yield. The process should yield a product that is free of by-products (e.g., undesired isomers, side-products and reagents). Shortcomings in any of the above parameters result in increased manufacturing costs, which impacts negatively on the desirability of the process.
The simplest synthetic approach to the N-9 substituted guanine compounds involves the direct alkylation of a protected guanine base. However, there are significant drawbacks to this approach. In many reported processes, guanine protected by acyl groups (for example, diacetylguanine) is employed as the protected guanine base. However, acyl groups may prove difficult to remove at the completion of the process, resulting in lower yields. Also, known alkylation processes are not regiospecific for the N-9 position of the protected guanine base, and result in a mixture of N-9 and N-7 alkylation products. The unwanted N-7 isomer is difficult to separate from the desired N-9 compound, requiring chromatography for isolation. Chromatographic separation on a commercial scale is most undesirable, because of the increased costs associated with such a separation (cost of solvents and stationary phase, low yields of desired product, etc).
Surprisingly, efficient and selective processes for preparing N-9 substituted guanine compounds, including ganciclovir and acyclovir, have been discovered. The processes are essentially specific for the preparation of the N-9 isomer, since the alkylation step provides a high N-9/N-7 ratio of alkylated guanine product (a ratio of greater than 30:1 may be achieved), thus eliminating the need for the chromatographic separation of the N-9/N-7 isomer mixture. The processes also provide high yields, require simple starting materials and reaction conditions, and are carried out from start to finish in a single reaction vessel, delivering acyclovir and ganciclovir in greater than 99% purity.
Previous processes for the preparation of acyclovir and similar compounds are disclosed in U.S. Pat. Nos. 4,355,032, 4,360,522, 4,621,140, and 5,250,535, European Patent Applications 152,965, 532878, and 72027, and JP 5213903. Syntheses of related compounds are disclosed in Nucleosides Nucleotides, 8 (2) , pp 225-256 (1989), Zhongguo Yaoke Daxue Xuebao, 23 (1) , pp 43-44 (1992), Org. Prep. Proced. Int, 25(4), pp 375-401 (1993), J. Med. Chem., 26(5), 759-61 (1983), Synth. Commun., 18(14), 1651-60 (1988), and Chem. Pharm. Bull., 36 (3), 1153-1157 (1988) .